Patients with end-stage renal disease (ESRD) suffer from an exceedingly high rate of cardiovascular mortality. ESRD patients have high baseline sympathetic nervous system (SNS) activity which contributes to their increased cardiovascular mortality and high blood pressure. The objective of this project is to elucidate mechanisms of SNS activation in this population, and develop therapies to ameliorate SNS hyperactivity and thereby decrease cardiovascular mortality. The hypothesis is that muscle deconditioning increases SNS activity in ESRD, and that exercise training may improve SNS activity and BP in these patients. The first aim is to determine if ESRD subjects exhibit abnormal skeletal muscle reflex activation of SNS activity leading to overall SNS hyperactivity. Specifically, blunting of metaboreceptor activation and augmentation of mechanoreceptor activation is expected in ESRD. SNS outflow will be compared between ESRD subjects and controls while arm tasks are performed to stimulate mechanoreceptors and metaboreceptors. The second aim is to determine if intradialytic exercise training improves baseline SNS hyperactivity and ambulatory blood pressure patterns in ESRD. If there is altered muscle reflex activation in patients with ESRD, we will also determine if exercise training restores metaboreceptor sensitivity and decreases mechanoreceptor sensitivity in these patients. ESRD subjects will be randomized to a thrice- weekly exercise intradialytic regimen versus remaining sedentary, and the effects of this intervention on SNS hyperactivity, ambulatory blood pressure patterns, and restoration of normal muscle mechanics, will be assessed. If intradialytic exercise training is found to be beneficial, this feasible, nonpharmacologic intervention may become an instituted therapy to decrease cardiovascular morbidity and mortality in the ESRD population. The goal of this research project is to discover causes for the high rate of death from heart disease in patients with kidney failure on hemodialysis. In patients with kidney failure, physical inactivity may contribute to heart disease by causing abnormal muscle reflexes that lead to increased adrenaline release and blood pressure. Therefore, aerobic exercise during hemodialysis may improve physical conditioning and decrease blood pressure and adrenaline release, thereby ameliorating the risk of death from heart disease in patients with kidney failure. [unreadable] [unreadable] [unreadable] [unreadable]